The Great Escape: Tumor-Suppressor Genes and Male-Female Cancer Disparity
Reply

Stand Up To Cancer’s Innovative Research Grant (IRG) recipients, early-career investigators who take fresh approaches to critical questions about cancer, continue to generate interesting and compelling research.

One of these IRGs is David M. Weinstock, MD, of Dana-Farber Cancer Institute and Harvard Medical School, who was awarded a grant to help develop a rapid system for the identification of molecular abnormalities that drive cancer causation. Recently he was part of a team that studied a puzzling question: Why is cancer more prevalent in men than women?

Glioblastoma, the most common type of brain cancer, occurs twice as often in men as in women, as does kidney and renal pelvis cancer and stomach cancer; liver cancer is even more likely to occur in men than women. Overall, men are 20 percent more likely than women to develop cancer, for reasons not fully understood.

The team came up with a possible explanation: Women have more copies of certain genes that fight cancer.

The sex of a human being is determined by the X and Y chromosomes. Men have one of each, so they are XY, while women have two X chromosomes, so they are XX. Since only one X chromosome is needed for proper development and growth, one of the female copies of the X chromosome is turned off. This process is called X-inactivation.

However, not all the genes on the chromosome are turned off. Some are said to “escape” from inactivation, and some of these play a role in suppressing tumors. The team named the gene set “escape from X-inactivation tumor suppressor” (EXITS) genes. The “escape” gives a woman an extra copy of some of these genes, an example of “biallelic expression,” whereas a man has only one copy.

To examine whether EXITS genes have anything to do with the greater predominance of cancer in men, the team studied alterations in genes that occurred during the patient’s life.

The team studied genetic sequencing data from more than 4,000 tumors across 21 different types of cancer, looking for genes that had mutations which caused the genes to lose their functions in human biology. They found six genes with loss-of-function mutations that are found more often in male tumors than female. Some of these genes are known to be tumor suppressor genes. Further, some of these mutations are known to be associated with glioblastoma and kidney cancer — which offers a potential mechanism for male bias in these tumor types.

“Male based mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon,” the team wrote in the journal Nature Genetics. “We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.”

Gene mutations in EXITS are not the only reason for the differences in cancer incidence in men and women, but this study offers insight into how specific genes play a role in sex-specific differences in tumor genetics.

The disparity in the burden of cancer between men and women has never been fully explained. The hypothesis that it may be linked to tumor suppressor genes that escape X-inactivation is potentially an important step forward in understanding this disparity. (Other scientists are suggesting that escape from X-inactivation may also help explain disparities in other conditions, such as lupus and certain neurological disorders.) The research on EXITS by Weinstock and others is an example of SU2C’s support for basic as well as translational research.